Morphine will lower intraocular pressure in humans, and conjunctival instillation of naloxone, a non-selective opioid receptor antagonist, will reverse the ocular hypotension. Moreover, opiate-like immunoreactivity has been detected throughout organs innervated by the automatic nervous system of humans and animals, including the eye, suggesting that endogenous opioid peptides participate in the neuroendocrine regulation of ocular hydrodynamics. This project will test the hypothesis that altered opioidergic activity is one factor that contributes to episodic ocular hypertension that eventually becomes sustained and subsequently damages the optic nerve head causing loss of visual field (glaucoma). Thus, alteration of the opioidergic system could result in dysfunction of ocular hydrodynamics, greater susceptibility to stress and enhanced predisposition to glaucoma. This hypothesis will be tested by examining the role of the opioid system (endogenous opioids and opioid receptors) in modulating ocular hydrodynamics. Experiments will be performed to: (1) characterize the activity of relatively selective opioid receptor agonists (kappa, delta) on intraocular pressure, aqueous inflow and outflow facility in rabbits; (2) determine sites and subtypes of opioid receptors in the anterior segment by evaluating the effects of opioid agonists and antagonists on tissues that regulate aqueous inflow and outflow; (3) examine, at the cellular level, the signal transduction mechanisms (cAMP/cGMP, GTP-binding proteins [G proteins], potassium and calcium channels, protein kinase C [PKC]) associated with opioid agonist-induced alterations in ocular function; and (4) assess whether endogenous opioid tone exists in the anterior segment by using: (a) simulated exercise to activate the opioid system, (b) inhibitors of opioid peptide catabolism, (c) selective depletion of co-transmitters and (d) antagonism of "dominant" receptors that mask effects of opioid agonists. Opioid-induced changes in sympathetic neurotransmitter release will be determined in two neuronal models, and signal transduction will be assessed utilizing isolated tissues (iris/ciliary bodies, superior cervical ganglia) and cultured cells (sympathetic nerves, ciliary epithelium, trabecular meshwork cells). This project should define the mode of action of opioid drugs on aqueous humor dynamics and offer evidence for mechanisms involved in altered opioid function as a contributor to the dysregulation of intraocular pressure in glaucoma. The ultimate goals of the project are to: (1) define the participation of the opioidergic system in ocular hydrodynamics, (2) gain evidence that dysfunction of this system contributes to the etiology of glaucoma syndromes and (3) provide a better understanding of the mechanisms of action of opioidergic drugs on opioid and non-opioid receptors in the eye which could aid in the design of innovative therapeutic approaches for the management of glaucoma.